Cancer is a serious disease that accounts for a major cause of death. However, therapeutic needs therefor have not yet been met. In recent years, in order to overcome the problem of conventional chemotherapy that causes damage even to normal cells, studies have been intensively conducted regarding cancer therapy using molecularly targeted agents, in which a drug targeting a specific molecule that is expressed specifically in a cancer cell is designed, and the therapy is then carried out using the drug.
CDH3 is a molecule in cancer cells that can be a target of molecular therapeutic agents (Non Patent Documents 1 and 2). CDH3 is a membrane protein that has been discovered as a molecule that is calcium-dependently associated with hemophilic cell adhesion (Non Patent Document 3). A protein, which has cadherin repeats (ECs) consisting of approximately 110 amino acid residues having high homology to one another, is referred to as a “cadherin superfamily.” There are 120 or more types of such proteins, and they play an important role in the maintenance of multicellular organization. CDH3 is a member belonging to such a cadherin superfamily.
It has been reported that the expression of CDH3 in cancer tissues is higher than that in normal tissues (Non Patent Documents 1, 2, and 4). In cancer therapy, it has been studied to use a drug formed by binding an anticancer agent to an anti-human CDH3 antibody or an antibody having antibody-dependent cellular cytotoxicity (ADCC) for cancer cells in which the expression level of CDH3 is high (Patent Documents 1 to 3).
In recent years, many antibody drugs for cancer therapy have been actually on the market as molecular targeted drugs, and these drugs have provided therapeutic effects. The principal modes of action of these drugs include inhibition of signals associated with cell survival or cell growth and antibody-dependent cellular cytotoxicity (ADCC).
It has been generally known that when an antibody derived from an animal other than a human, such as a mouse antibody, is administered to a human, the administered antibody is recognized as a foreign substance, so that a human antibody against the mouse antibody (Human Anti Mouse Antibody: hereinafter referred to as “HAMA”) is induced in the human body. It has been known that the HAMA reacts with the administered mouse antibody, and causes side effects (Non Patent Documents 5 to 8) or accelerates the disappearance of the administered mouse antibody from the body (Non Patent Documents 6, 9 and 10), thereby reducing the therapeutic effects of the mouse antibody (Non Patent Documents 11 and 12).
In order to overcome these problems, an attempt has been made to produce humanized antibodies, such as humanized chimeric antibodies or humanized complementarity determining region (hereinafter referred to as CDR)-grafted antibodies, from antibodies of animals other than humans by utilizing gene recombination technology. The humanized chimeric antibody means an antibody, in which the variable region (hereinafter referred to as a “V region”) is the antibody of an animal other than a human and the constant region (hereinafter referred to as a “C region”) is a human antibody (Non Patent Document 13). The humanized CDR-grafted antibody means an antibody, in which the amino acid sequence of CDR in the V region of the antibody of an animal other than a human is grafted into a suitable position of a human antibody (Non Patent Document 14). When compared with antibodies derived from animals other than humans, such as a mouse antibody, such humanized antibodies have various advantages for clinical application to humans. For example, with regard to immunogenicity and stability in blood, it has been reported that, upon administration of a humanized chimeric antibody to a human, the half-life in blood of the humanized chimeric antibody had been longer than that of a mouse antibody by approximately 6 times (Non Patent Document 15). In an experiment using monkeys, it has been reported that the immunogenicity of a humanized CDR-grafted antibody had been lower than that of a mouse antibody, and that the half-life in blood of the humanized CDR-grafted antibody had been longer than that of the mouse antibody by approximately 4 to 5 times (Non Patent Document 16). That is to say, a humanized antibody is anticipated to have fewer side effects than antibodies derived from animals other than humans and to maintain its therapeutic effects for a long period of time. In addition, cytotoxicity mediated by an Fc region of an antibody (a region that follows a hinge region on the heavy chain of an antibody), such as complement-dependent cytotoxicity (hereinafter referred to as “CDC activity”) or antibody-dependent cellular cytotoxicity (hereinafter referred to as “ADCC activity”), is important to achieve therapeutic effects. Since the Fc region of a human antibody has a higher affinity for a human complement component or for an Fc receptor present on the surface of a human immune system effector cell as compared with the Fc region of a mouse antibody, it can be anticipated to provide more therapeutic effects. For instance, an increase in tumor cytotoxicity by human effector cells has been reported with regard to a humanized chimeric antibody in which the Fc region of a mouse antibody against GD2 is replaced with the Fc region of a human antibody (Non Patent Document 17). In addition, the same results as described above have been reported regarding a humanized CDR-grafted antibody against a CAMPATH-1 antigen (Non Patent Document 18). The aforementioned results demonstrate that a recombinant antibody is more preferable as an antibody for use in clinical application to humans, than an antibody derived from an animal other than a human.
Further, as a result of recent advances in the protein engineering and the genetic engineering, it has become possible to produce antibody fragments each having a small molecular weight, such as Fab, Fab′, F(ab)2, a single-chain antibody (hereinafter referred to as an “scFv”) (Non Patent Document 19), and a disulfide-stabilized V region fragment (hereinafter referred to as a “dsFV”) (Non Patent Document 20). Since these fragments have a molecular weight smaller than that of a complete antibody molecule, they are excellent in terms of transitivity to target tissues (Non Patent Document 21). Regarding these antibody fragments as well, a fragment derived from a recombinant antibody is more preferable as an antibody for use in clinical application to humans.